Public Viewpoints on the Evolution of Biologicals Research and Development RONALD W. LAMONT-HAVERS such demagoguery. The truth is, rather, that much of the knowledge which will produce more effective biologics in the future still is locked within the mysteries of the cellular mechanism. The understanding of these mnechanisns can only be obtained by the accretion of knowledge based upon former discoveries and intuitive insight obtained through the support of broadly based investigation. The extent and cost of such investigations can only be supported in large part through govemment investment, since the application of that knowledge-and there certainly will be an application-may be decades in the future. The application of thii knnwl^lia tn thA rn* whsra biological product useful in man would seem to be an achievable goal must also be the major responsibility of government since the relationship of the investment of resources to the possibility of success may be minimal. Because of the cost involved, the continued investment by government in the further development of the biologicals through the early clinical trials and the field trials is now essential. Only when the effectiveness of a biological is proven and the support of government health officials is assured can a pharmaceutical company afford to make a major investment. It has been evident over the past decade that pharmaceutical manufacturers have been decreasing their interest in, and commitment to, development of new biologicals or even contmuation of their former levels of commitment.

Govemnments generally have need to ensure the health of their citizens. One of the more fundamental concerns is that of protection against epidemic and infectious diseases. Generally speaking, this concern was originally expressed by the establishment of competence in epidemiology, methods of detection, and means of quarantine. All of these activities are of necessity the responsibility of some central govemment. As the limitations of the methods of detection and quarantine were appreciated, the govemments sought the means not only to improve such competence but to explore more effective methods of control. Society has been encouraged in the support of such efforts, since the relationship of the entire spectrum of biomedical knowledge (basic research, applied research, development, and application) to lowering the economic cost of health care is nowhere so self-evident as in the research and development of biologicals. Certainly the marked effects on the health care delivery system are well exemplified by the development of the polio vaccine which eliminated the expensive, halfway technology of iron lungs and by the rubella vaccine which resulted in the marked reduction in the expensive, chronic effects of rubella in utero. While it is common, at least in the United States, to hear the charge that the results of research are sitting on some shelf rather than being immediately shifted into the health area, there is, indeed, no evidence to substantiate

Deputy Director, National Institutes of Health. U.S. Department of Health, Education, and Welfare, Bethesda, Maryland, U.S.A.

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R. W. Lamont-Havers

A number of companies have dropped biologicals production alto,gether. During the last decade there has been little research and devel-

review by scientists competent to make judgments in the particular field under discussion. In order that the recommendations resulting

opment in the pharmaceutical industry on vaccines to prevent such universal afflictions as the common cold, pneumococcal pneumonia, meningococcal and gonococcal infections, influenza, mycopla3ma pneumonia, respiratory syncytial virus infection or parainfluenza, except as financed and sponsored by government ageiwdes. Only one company in the United States has shown real interest in and been active in development of a hepatitis B vaccine. Comr panies have stopped producing such diagnostic adjuncts as pneumococcal and streptococcal typing sera, as well as nrckettsial diagnostic sera. It would seem logical that a society should be concerned with regard to the safety, potency, and efficacy of products which are admiunstered to prevent or treat disease. It is also evident that when one is dealing with areas ofsuch deep importane to society as biologicals, government must have the responsibility of assuring that biologicals offered to the public are safe, will perforn as expected, and are properly used. This involves the establishment of standards for purity and potency and the testing of products to assure that they meet these standards, as well as the monitoring of advertising or other means of advising physicians, health workers, and the public on proper usage. There is continuous research with regard to the establishment of the standards used in tests in order to increase performance, to introduce new, less expensive, and more accurato tests, and to meet new problems such as those related to the fmding of bacteriophages in poLio and other live vaccines. The public sctor, as a major supporter of research and development, must be assured that the investment of public monies is for projects of scientific merit and that there is some means of accountability and evaluation of the results of that expenditure. The establishment of the scientific merit and feasibility of any particular program which is to be supported can best be judged through peer

from such a peer review can, indeed, withstand the scrutiny of credibility, the reviewers should not be employees of the funding agency, nor should the official responsible for funding and managing the program be responsible for managing the review process. In addition to the funding and management of the immediate programs in biologicals research and development, governments must be concerned with the manner in which the future is being protected. If other mechanisms within society are not sufficient for the replenishment, renewal, and necessary redirection and expansion of its scientific pool, then government must intervene directly by the support of training mechanisms. In biologicals research designed to improve the health of man, the ultimate subject of such research must be the human. While extensive information can be obtained by the use of nonviable systems and various animal models, including the subhuman primate, ultimately the safety and efflcacy of any biologic must be tried in human volunteers and in human patients.

During the past number of years, many societies have shown increasing concern for the rights of individuals, involving a wide spectrum of issues. As part of this generaI movement, particular emphasis has been given to the protection of the rights of subjects of biomedical research. Much of this concern revolves around the problem of obtaining full consent and the weighing of benefit-to-risk ratios. During the 1960's, attention was given to the establishment of procedures by which this protection could be monitored and supervised. These procedures were based on the assumption that the subject was a mentally competent, free-living adult or could be properly represented by parent, relative, or legal guardian. Increasingly in the last few years, concern has been expressed with regard to the protection of particular segments of our populations in which

Public Viewpoints on the Evoiuto of Biiogicais Reseach and Development

obtaining consent is perceived as presenting major problems. The particular populations receiving most attention are those made up of children, prisoners, and the mentally disabled. The use of children as subjects presents speci problems. It is recognized, for example, that children cannot be thought of physiologically as small adults in trying to predict their responses to a therapeutic or preventive intervention. Thus, any new biological which nmight benefit them must mdeed be tested upon children for efficacy and safety. It is, however, generally impossible or impractical to expect a child to comprehend sufficiently to give an "informed consent" even though there is no standard definition of a "child" or even common recognition of when the "age of consent" is reached. There is also no general agreement, at least in English common law, as to responsibility of the parent or guardian with regard to giving consent on behalf of the child. In the case of research of a new form of therapy of possible benefit to that child, particularly if this should be potentially lifesaving, there is general agreement that the consent of the parent or guardian should be accepted. In a situation involving so-caled "nontherapeutic research" the situation is much less clear. It is felt by many, at least in the United States, that the parents or guardian cannot give consent to any procedure, not of clear and present benefit to that child. In this state of confusion, it is felt by many that the only way in which consent for nontherapeutic research on children can be obtained would be through the courts acting for society. Various methods are being tried to ameliorate the problems reLating to obtaining consent for nontherapeutic research involving children, such as review by ethical review boards and the establishment of patient review committees. If we are to continue with the development and introduction of biologicals of benefit to children, it is essential that this problem be resolved in a way which will permit progress. An illustration of this problem is given by the approach to the development of a vaccine

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against respiratory syncytial virus-a major cause of bronchiolitis in infants, with a considerable fatality rate, especially if expert medical care is not available. Killed vaccines have been thoroughly explored and have been found to potentiate the illness rather than prevent it Local immunization of the respiratory tract is needed. Attenuated viruses would first have to be administered to adults to determine safety and infectivity and then gradually worked down through successively younger age groups until the target population-infants under the age of six months-is reached. The risks of direct introduction into that age group without first testing in older individuals would be unacceptable. Yet, the older individual is not benefited since the clinical disease is confined to infants in the period before they develop immunity as a result of infection-that is, birth to two years of age. The use of prisoners which, in the United States at least, has been traditional for many phases of clinical investigation of biologicals is now being reexamined. It is argued that, since one can never be assured that the consent of prisoners has been given freely and without inducement, prisoners should never be used as subjects in biomedical research unless it is directly related to the effects of their imprisonment. This obviously is a very simplistic view of a very complex problem. This topic is coming under intensive review by the Commission on the Protection of Human Subjects of Biomedical and Behavioral Research which was established by the United States Congress in 1974. It is likely. however, that, certainly in the United States, less and less clinical investigations involving biologicals will be done on prisoner populations. This is not only because of the presumed moral and ethical problems involved but, to an even greater extent, because of the increasing difficulties that this population is presenting, in large part due to the changing attitude of the prisoners themselves. While the nonutilization of prisoners will probably not seriously hamper future research and developrnent of biologicals, it will increase

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the cost of such reseach and development as more acceptable populations are identified and utilized. Similarly, the protection of the rights of the institutionalized mentally disabled, in which obtaining consent presents major problems, is being given careful consideration. Certainly it is clear that the use of such populations will be allowed only in the development of those biologicals which are clearly related to diseases indigenous to that population. Of late, the governmnents have become concerned with two other aspects of research and development utilizing human subjects. The first deals with the problem of compensation of a research subject who becomes injured as a result of the procedures being performed. In particular, this would be where the injury was the result of an unforeseen problem arising from the experimental procedure and not from negligence on the part of the investigator or supporting staff. A recent survey would indicate that while such injuries are relatively rare, particularly in the nontherapeutic research, they do occur. An area of equal concern is that of protecting the manufacturer of a biological from malpractice suits when, during the course of a field trial or indeed utlization of a vaccine approved by the government for a preventive program, a disease such as poliomyelitis is contracted by the patient even though this cannot be shown to be the result of the administered vaccine itself. This raises an Issue with which the government needs to become involved. It is possible for governmental regulations relating to the production of biologicals and testing of these biologicals in human populations (as well as the risk of malpractice claims against manufacturers) may become so excessive that the development and manufacture of biologicals by the private sector would no longer be economically feasible. Under these circumstances, the government will need to institute corrective, supportive, and protective actions. A problem of increasing magnitude to those in government responsible for support of bio-

medical research is the availability of sufficient quantities of subhuman primates for use in research. The concern for protection of endangered species in their native lands has resulted in a restriction of supply at a time of increased utilization of the subhuman primate in fundamental, applied, and developmental research, as well as in the area of control for efficacy and safety of biologics. In the future, governments will become even more involved in monitoring the importing of these species and placing some type of control and regulation on their utilization. The need to establish breeding colonies, not only in the importing country but by supporting such installations in the native countries of the species, will become of great importance. Such activities will require negotiations on the government-to-government level as well as governmental negotiations with organizations such as the World Health Organization (WHO). The forward progress of science is nurtured and accelerated in proportion to the number of intuitive, prepared, and innovative human minds that become involved in a particular problem. This involvement can only occur through adequate communication of scientific knowledge. Thus, certainly in the area of biomedical research, it is in the best interest of society that information concerning the research and development which they are supporting is disseminated as quickly and as efficiently as possible through the various mechanisms of workshops, symposia, publications, and even more effectively, by personal contact of scientist-to-scientist interchange. The mechanisms by which research and development are supported must be adequate to span the need for free-ranging, innovative production of general knowledge on the one hand, and obtaining carefully specified, sharply delineated knowledge or products on the other. Such a range of activities can be supported through fully owned and operated government laboratories and facilities or through the utilization of nongovermmental facilities and institutions. When nongovernmental facilities are utilized it is traditional, at least within the

Public Viewpoints on the Evolution of Biologcals Research and Development

United States, to support research and development through either the grant or contract mechanism. It is felt, however, that the grant mechanism (which has been characterized as a "gift in aid") is best suited for the investigatorinitiated research project involving the development of new knowledge, from fundamental research through to human investigation. The contract, on the other hand, is thought to be the mechanism of choice when the awarding agency believes that the protocols, particularly of cooperative clinical trials, need more careful scrutiny, coordination, and central control. It is thought to be the only mechanism of support where the end product, such as a vaccine, can be carefully delineated and the product, in effect, bought. In actual fact, however, either the grant or contract mechanism can be used to produce any desired result, depending upon the conditions of the award. The important thing is the intent of the awarding agency rather than the instrument. The intent, then, is to stimulate new, innovative knowledge on the one hand, and the development of a known product on the other. The "conditions" which the awarding agency can impose with regard to the conduct of the research are an important aspect of support. Thus, the guidelines and regulations which the United States Government has promulgated with regard to the protection of the rights of human subjects initially applied only to those subjects who were participating in a Federallysupported project. These guidelines were soon being applied by institutions, on a voluntary

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basis, to all projects within their jurisdiction, whether Federally funded or not. This voluntary extension later became mandatory when the Federal Government stated that it would consider withholding Federal funds from any institution where there was evidence that the protection of the rights of individuals participating in research, regardless of the source of support, was not being effectively monitored. In this paper I have stressed the need for government to support biologicals research and development as a clear benefit to its own people. There should be recognition, however, that the advanced technologies of some countries enable them to perform research and development on biologicals which are potentially useful against diseases and which are not a threat to the populace of that country, e.g., cholera vaccine research in the United States. Governments, where they are able, must assume such responsibilities, if not as "good Samaritans," then out of recognition that disease does not respect national boundaries and therefore what is someone else's problem today may be yours tomorrow. This conference will be considermg topics of deep concern to the public sector as society seeks to protect itself from the ravages of disease. The discussions, expositions, and recommendations of this group will be of great help as the policies and regulations relating to research. development. and use of biologicals are reviewed, modified, and extended by govemmmental bodies in the future.

Public viewpoints on the evolution of biologicals research and development.

Public Viewpoints on the Evolution of Biologicals Research and Development RONALD W. LAMONT-HAVERS such demagoguery. The truth is, rather, that much o...
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